VCV001284647.8 - ClinVar

NM_000237.3(LPL):c.286G>C (p.Val96Leu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000237.3(LPL):c.286G>C (p.Val96Leu)

Variation ID: 1284647 Accession: VCV001284647.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p21.3 8: 19951805 (GRCh38) [ NCBI UCSC ] 8: 19809316 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 25, 2021	Sep 29, 2024	Sep 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000237.3:c.286G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000228.1:p.Val96Leu	missense
NC_000008.11:g.19951805G>C
NC_000008.10:g.19809316G>C
NG_008855.2:g.55089G>C
LRG_1298:g.55089G>C
LRG_1298t1:c.286G>C	LRG_1298p1:p.Val96Leu

... more HGVS ... less HGVS

Protein change

V96L

Other names

Canonical SPDI

NC_000008.11:19951804:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00010

Trans-Omics for Precision Medicine (TOPMed) 0.00010

Exome Aggregation Consortium (ExAC) 0.00012

The Genome Aggregation Database (gnomAD) 0.00013

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

dbSNP: rs373088068 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LPL		-	-	GRCh38 GRCh37	780	869

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 16, 2024	RCV001699858.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jan 11, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003440831.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 7912254‚ 27055971‚ 29748148 Comment: This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 96 of the LPL protein (p.Val96Leu). … (more) This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 96 of the LPL protein (p.Val96Leu). This variant is present in population databases (rs373088068, gnomAD 0.02%). This missense change has been observed in individual(s) with lipoprotein lipase deficiency (PMID: 7912254, 27055971, 29748148). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Val69Leu. ClinVar contains an entry for this variant (Variation ID: 1284647). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LPL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LPL function (PMID: 7912254). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Likely pathogenic (Sep 16, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001986345.3 First in ClinVar: Nov 06, 2021 Last updated: Sep 29, 2024	Comment: Identified in the heterozygous state in individuals with hypertriglyceridemia in published literature and in unrelated patients with hypertriglyceridemia referred for genetic testing at GeneDx (PMID: … (more) Identified in the heterozygous state in individuals with hypertriglyceridemia in published literature and in unrelated patients with hypertriglyceridemia referred for genetic testing at GeneDx (PMID: 36411388, 36476373, 29555771, 27055971, 22239554); Published functional studies demonstrate reduced enzyme activity compared to wild-type (PMID: 7912254); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22239554, 29555771, 29748148, 31980526, 36325899, 36476373, 36411388, 7912254, 27055971, 32041611) (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001922390.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001962842.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021

Comment:

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 96 of the LPL protein (p.Val96Leu). This variant is present in population databases (rs373088068, gnomAD 0.02%). This missense change has been observed in individual(s) with lipoprotein lipase deficiency (PMID: 7912254, 27055971, 29748148). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Val69Leu. ClinVar contains an entry for this variant (Variation ID: 1284647). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LPL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LPL function (PMID: 7912254). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

Identified in the heterozygous state in individuals with hypertriglyceridemia in published literature and in unrelated patients with hypertriglyceridemia referred for genetic testing at GeneDx (PMID: 36411388, 36476373, 29555771, 27055971, 22239554); Published functional studies demonstrate reduced enzyme activity compared to wild-type (PMID: 7912254); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22239554, 29555771, 29748148, 31980526, 36325899, 36476373, 36411388, 7912254, 27055971, 32041611)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and biochemical features of different molecular etiologies of familial chylomicronemia.	Hegele RA	Journal of clinical lipidology	2018	PMID: 29748148
Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency.	Rodrigues R	Journal of clinical lipidology	2016	PMID: 27055971
A compound heterozygote for lipoprotein lipase deficiency, Val69-->Leu and Gly188-->Glu: correlation between in vitro LPL activity and clinical expression.	Bruin T	Journal of lipid research	1994	PMID: 7912254

Text-mined citations for rs373088068 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000237.3(LPL):c.286G>C (p.Val96Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs373088068 ...